Sudden cardiac arrest is a problem of public health magnitude affecting 330,000 individuals annually in the United States with an averaged survival rate of only 7%. Return of cardiac activity requires reperfusion of ischemic tissues with oxygenated blood. Yet, reperfusion concomitantly activates multiple pathogenic mecha- nisms, collectively known as reperfusion injury. Current resuscitation methods do not include interventions that could ameliorate such injury. Yet, the discovery that erythropoietin activates potent cell protective mecha- nisms (many of which converge on mitochondria) may provide the means to ameliorate such injury during car- diac arrest and to establish a novel paradigm for cardiac resuscitation. We have reported in a rat model of ventricular fibrillation (VF) and closed-chest resuscitation that erythropoietin elicits favorable myocardial effects that result in hemodynamically more effective chest compression and im- proved post-resuscitation hemodynamic function. Moreover, in a recently clinical trial conducted in collabora- tion with colleagues in Slovenia, administration of erythropoietin was associated with increased rate of initial resuscitation and increased rate of survival to hospital discharge. We hypothesize that administration of erythropoietin rapidly activates non-genomic cell protective mechanisms prompting mitochondria to resist reperfusion injury and remain bioenergetically functional, resulting during car- diac resuscitation in: 1) preservation of left ventricular myocardial distensibility enabling hemodynamically more effective CPR and higher resuscitation rates and 2) better post-resuscitation myocardial function yielding - in conjunction with higher resuscitation rates - higher rates of neurologically intact survival. We propose to use first an open-chest pig model of VF and extracorporeal circulation allowing precise control of coronary perfusion pressure and direct access to the myocardium to investigate: (1) whether erythropoietin prevents deterioration of mitochondrial bioenergetic function enabling preservation of left ventricular compli- ance during VF and preservation of left ventricular function after return of spontaneous circulation, (2) whether these effects are mediated through activation and mitochondrial translocation of PKC5 and Akt leading to pres- ervation of mitochondrial respiration, and (3) whether the effects of erythropoietin vary contingent on coronary blood flow, given the inconsistent quality of manual CPR and the increasing availability of hemodynamically more potent CPR methods. We will then use a pig model of VF and closed-chest resuscitation to examine the effects of erythropoietin in the presence or absence of concomitant administration of epinephrine on the hemo- dynamic efficacy of chest compression, initial resuscitation, post-resuscitation myocardial function, and 72-hour survival with intact neurological function. Demonstration that erythropoietin preserves mitochondrial bioenergetic function leading to functional myocar- dial benefits for resuscitation would be novel and facilitate the planning and conduct of additional clinical trials, and eventual clinical implementation. PUBLIC HEALTH RELEVANCE: Nearly 330,000 individuals suffer an episode of sudden cardiac arrest every year in the United States. Many of these individual are Veterans given the high prevalence of coronary artery disease and underling risk factors such as smoking, hypertension, high cholesterol, and diabetes mellitus. Current resuscitation techniques fail to promote neurologically intact survival in more than 7% of these individuals. New and more effective treatments for sudden cardiac arrest that will enable a substantially higher number of individuals to survive without organ dysfunction are urgently needed. This application will examine one approach for improving resuscitation from cardiac arrest by administration of erythropoietin during cardiopulmonary resuscitation. Erythropoietin is a naturally occurring hormone that has been shown in recent studies to help the heart and other organs resist the injury caused by lack of blood flow. Successful development of this new approach to cardiac resuscitation could lead to thousands of lives saved every year in the United States and many more worldwide.